WO2020011870A1 - Solution saline activée électrochimiquement - Google Patents

Solution saline activée électrochimiquement Download PDF

Info

Publication number
WO2020011870A1
WO2020011870A1 PCT/EP2019/068574 EP2019068574W WO2020011870A1 WO 2020011870 A1 WO2020011870 A1 WO 2020011870A1 EP 2019068574 W EP2019068574 W EP 2019068574W WO 2020011870 A1 WO2020011870 A1 WO 2020011870A1
Authority
WO
WIPO (PCT)
Prior art keywords
ecas
salt solution
electrochemically activated
activated salt
treated
Prior art date
Application number
PCT/EP2019/068574
Other languages
English (en)
Inventor
Mihran Baronian
Fabio Carli
Elisabetta Chiellini
Ernest BAEHLER
Original Assignee
Azad Pharma Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Azad Pharma Ag filed Critical Azad Pharma Ag
Priority to CA3104618A priority Critical patent/CA3104618A1/fr
Priority to US17/259,458 priority patent/US20210275579A1/en
Priority to AU2019302997A priority patent/AU2019302997B2/en
Priority to KR1020217000792A priority patent/KR20210031689A/ko
Priority to CN201980046368.2A priority patent/CN112805064A/zh
Priority to EP19740518.6A priority patent/EP3820568A1/fr
Priority to JP2021524110A priority patent/JP2021531341A/ja
Publication of WO2020011870A1 publication Critical patent/WO2020011870A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B1/00—Electrolytic production of inorganic compounds or non-metals
    • C25B1/01—Products
    • C25B1/24—Halogens or compounds thereof
    • C25B1/26—Chlorine; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B11/00—Electrodes; Manufacture thereof not otherwise provided for
    • C25B11/02—Electrodes; Manufacture thereof not otherwise provided for characterised by shape or form
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application refers to an electrochemically activated salt solution (ECAS), its production, and its use for treating infections.
  • ECAS electrochemically activated salt solution
  • Electrochemically activated salt solutions are usually obtained by electrolysis of sodium chloride solutions. Electrochemically activated salt solutions are known as cleaning or disinfection agents e.g. in agriculture, dentistry, medicine and food industry. It can be used in applications like surface disinfection, e.g. of working plates, tables, floors, etc., for cold sterilizing procedures in agriculture, for the elimination of microbial organisms, for wash and laundry application, in swimming pools and even as prophylaxis against athletes foot.
  • WO 2004/031077 discloses a device for producing a biocidal solution by electrolytic treatment of an aqueous salt solution.
  • WO 2005/065388 discloses an oxidative reduction potential water solution and its use as disinfectant of a wound treatment.
  • JP 1997/0040444 discloses an acidic ECAS having a pH from 2.0 to 6.0 for use as an ophthalmic preparation.
  • US 2010/0330204 discloses an acidic ECAS having a pH from 1 .0 to 4.0 for the treatment of an outer eye disorder selected from cataract, ocular keratitis, corneal neovascularization, epithelium deficiency, and chronic opacity.
  • WO 2009/013019 discloses two-phase pharmaceutical preparations comprising an active ingredient and an ECAS for medical applications. ECAS is also suggested as a carrier for the manufacture of pharmaceutical preparations.
  • Ocular infections may cause serious ocular problems with significant sight-threatening consequences if - mostly aggressive - therapy is not promptly instituted.
  • cephalosporins and aminoglycosides have been used as first choice treatment for infectious eye diseases.
  • problems associated with topical antibiotics and the emergence of antibiotic-resistant organisms have prompted interest in the search for therapeutic alternatives (Romanowski et al., 2005, Willcox, 201 1 ).
  • preservatives such as benzalkoniumchloride (BAK)
  • BAK benzalkoniumchloride
  • preservative-free medicaments are usually offered only in single-use units.
  • preservative-free formulations typically have an acidic pH value of less than 5, while the recommended pH value of ophthalmica is neutral to slightly alkaline to avoid irritations of the eye and to enable high patients’ compliance.
  • the object of the present invention is the provision of an effective medicament which is stable over a prolonged period of time and improves the patients ' compliance by minimizing any harmful side effects, when applying the same.
  • the present invention refers to an electrochemically activated salt solution (ECAS) comprising
  • a content of total chlorine of between 1 and 500 mg/I, preferably of between 100- 450 mg/I,
  • the ECAS of the invention may further comprise at least one (salt of) boric acid and/or at least one (salt of) phosphoric acid.
  • the ECAS of the invention preferably further comprises at least one salt of boric acid and/or at least one salt of phosphoric acid, more preferably at least one salt of phosphoric acid.
  • the ECAS of the invention further comprises at least one salt of boric acid.
  • the ECAS of the invention further comprises at least one salt of boric acid and at least one salt of phosphoric acid.
  • Salts of boric acid are usually borates (B0 3 3 ).
  • Salts of phosphoric acid may include phosphate (P0 4 3 ), hydrogenphosphate (HP0 4 2 ) and/or dihydrogen phosphate (H 2 P0 4 ).
  • Suitable counterions of the above salts are alkali ions, such as sodium (Na + ) and potassium (K + ), ammonium (NH * ), or Ca 2+ .
  • the ECAS of the invention further comprises sodium dihydrogenphosphate and disodium hydrogenphosphate.
  • the (salt of) phosphoric acid - if present - is preferably present in a total amount of 0.01- 1000 g/l, more preferably in a total amount of 0.1-100 g/l.
  • the (salt of) boric acid - if present - is preferably present in a total amount of 0.01 to 1000 g/l, more preferably in a total amount of 0.1 -500 g/l.
  • the electrochemically activated salt solution is preferably stable over one year, more preferably over two years, when stored in a closed high-density polyethylene (HDPE) container at 20 °C.
  • HDPE high-density polyethylene
  • ECASs comprising at least one (salt of) boric acid and/or at least one (salt of) phosphoric acid may even improve the stability of the ECAS of the invention as compared to ECASs of the invention lacking at least one (salt of) boric acid and/or at leat one (salt of) phosphoric acid.
  • HDPE high-density polyethylene material
  • LDPE low density polyethylene
  • PP polypropylene
  • “stable” or“stability” in the sense of the present invention means that the redox potential of the ECAS of the present invention is reduced by 20%, preferably 1 - 10% at maximum after 6 months of storage under the respective storing conditions. Alternatively, the redox potential of the ECAS of the present invention is reduced by 25%, preferably 1-10%, at maximum after 12 months of storage under the respective storing conditions. Alternatively, the redox potential of the ECAS of the present invention is reduced by 30%, preferably 2-15%, at maximum after 24 months of storage under the respective storing conditions.
  • the redox potential can be determined via established methods known to the skilled person.
  • the ECAS according to the present invention may contain hypochlorite ions and/or hypochlorous acid, particularly in a total concentration of 1 to 10000 mg/I, more preferably in a total concentration of 10 to 1000 mg/I.
  • the total content of chlorite and/or chlorate ions is preferably below toxic levels, e.g. less than 10 mg/I, more preferably 0.001-10 mg/I, even more preferably 0.001 -4 mg/I.
  • the total content of heavy metals and heavy metal ions in the ECAS according to the invention is preferably below toxic levels, e.g. less than 10 pg/g, preferably less than 6 pg/g, more preferably between 0.001 and 6 pg/g, and the content of each individual heavy metal and heavy metal ion is preferably less than 0.5 pg/g.
  • Heavy metals and heavy metal ions may be or derive from silver, arsenic, gold, iridium, palladium, platinum, rhodium, thallium, cadmium, cobalt, mercury, lead, ruthenium, chromium, molybdenum, antimony, tin copper, nickel, osmium, or vanadium.
  • the heavy metal (ion) may be detected by ICP- MS analysis according to ISO 17025.
  • the ECAS of the invention may contain at least one viscosity- increasing agent, such as a polymer.
  • a polymer Any polymer may be used either organic or inorganic. Suitable polymers may be cellulose, cellulose derivatives, such as carboxymethyl cellulose (CMC), or hydroxypropyl methylcellulose (HPMC), polysaccharides, such as glucosaminoglycans, e.g. hyaluronic acid (HA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), silica gel, magnesium metasilicate and/or aluminum- metasilicate.
  • CMC carboxymethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • polysaccharides such as glucosaminoglycans, e.g. hyaluronic acid (HA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), silica gel, magnesium metasilicate and/or
  • the ECAS of the invention preferably does not contain, i.e. is free of, an additional therapeutically active agent, such as a drug. It has surprisingly been found that the ECAS of the invention is effective in the treatment of eye infections without the need of additional therapeutically active agents.
  • the ECAS of the invention preferably does not contain, i.e. is free of, an additional preservative, such as BAK, sodium perborate, oxychloro complex, zinc borate complex, etc. It has surprisingly been found that the ECAS of the invention has sufficient disinfecting power per se to prevent microbial growth.
  • the present invention relates to a process for producing an electrochemically activated salt solution (ECAS) as described above comprising the steps of
  • the electrolysis reactor preferably includes a cylindrical cathode, which is mounted coaxially within a cylindrical anode.
  • the cathode and the anode may be separated by a microporous membrane, wherein an electrical current is applied to the electrodes.
  • the electrolysis is conducted at a current of 10.0-30.0 A, preferably at a current of 15.0-20.0 A.
  • the electrolysis reactor is preferably configured for continuous electrolysis. One or more of said reactors can be combined in parallel or serially.
  • the aqueous chloride solution used in step (i) preferably has a concentration of up to 10 g/l, preferably 2-9 g/l, in water for injection (sterile water).
  • the ECAS obtained in step (i) or (ii) may be diluted with an aqueous medium, preferably sterile water.
  • the ECAS obtained in step (i) or (ii) may e.g. be diluted with an aqueous medium in a ratio of ECAS:aqueous medium of from 1 :6 to 6:1 , preferably 1 :0.5 to 1 :3.
  • the present invention relates to a pharmaceutical preparation comprising an electrochemically activated salt solution (ECAS) of the invention and optionally at least one therapeutically effective agent.
  • ECAS electrochemically activated salt solution
  • the pharmaceutical preparation according to the invention may comprise at least one pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients may be selected from e.g. buffers, adjuvants, auxiliary agents, fillers, diluents, etc.
  • the electrochemically activated salt solution (ECAS) of the invention is for use in treating infections, particularly eye infections, e.g. caused by microbes such as bacteria, fungi and/or viruses.
  • Bacterial and fungal infections might be caused by one or more species selected from the group consisting of Staphylococcus aureus, methicillin- resistant Staphylococcus aureus (MRSA), Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Enterobacter aerogenes, Streptococcus anginosus, Streptococcus pyogenes, Candida albicans, Aspergillus brasiliensis, Aerratia marcescens and Acinetobacter pitii.
  • MRSA methicillin- resistant Staphylococcus aureus
  • Escherichia coli Staphylococcus epidermidis
  • Viral infections might be caused by viruses selected from the group consisting of adenoviruses, such as human adenovirus B and human adenovirus C, enteroviruses, such as enterovirus 70 or coxsackie viruses, and herpesviruses, such as Herpes simplex virus 1 and Herpes simplex virus 2.
  • adenoviruses such as human adenovirus B and human adenovirus C
  • enteroviruses such as enterovirus 70 or coxsackie viruses
  • herpesviruses such as Herpes simplex virus 1 and Herpes simplex virus 2.
  • the electrochemically activated salt solution (ECAS) of the invention can be particularly used for treating eye infections preferably for treating conjunctivitis, keratitis, blepharitis, endophthalmitis, more preferably keratitis and/or conjunctivitis, even more preferably conjunctivitis. It was surprisingly found that the ECAS of the invention revealed optimum efficacy in the treatment of bacterial conjunctivitis and bacterial keratitis by in vitro and in vivo studies without causing detrimental side-effects. Thus, in a very preferred embodiment, the electrochemically activated salt solution (ECAS) of the invention can be used for treating conjunctivitis, e.g. caused by microbes, e.g. bacteria, fungi or viruses, more preferably for treating bacterial conjunctivitis.
  • microbes e.g. bacteria, fungi or viruses
  • the electrochemically activated salt solution (ECAS) of the invention can be used for treating keratitis, e.g. bacterial keratitis.
  • the electrochemically activated salt solution (ECAS) of the invention may be administered topically onto the eye, the lacrimal sac and/or the lid.
  • the ECAS of the invention may be administered onto the eye directly after infection.
  • Figure 1 Titer of the HSV-1 strain Kupka. Vero cells were treated with the test products (24 h and 2 h before infection, during infection, 2 and 6 h post infection), and infected with HSV-1 strain Kupka at a multiplicity of infection (MOI) of 0.01 . The infected cells were collected at 24 hours post infection (hpi) and the virus titer was determined by plaque assay. MOCK - infected untreated cells; 1 : 1 - infected cells treated with the ECAS2 diluted 1 :1 , 100 mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2, 100 mI; ACV - infected cells treated with aciclovir, 100 mM.
  • MOCK - infected untreated cells 1 : 1 - infected cells treated with the ECAS2 diluted 1 :1 , 100 mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2,
  • FIG. 2 Titer of the HSV-1 strain ANGpath.
  • Vero cells were treated with the test products 24 h and 2 h before infection, during infection, 2 and 6 h post infection, and infected with HSV-1 strain ANGpath at a MOI of 0.01 .
  • the infected cells were collected 24 hpi and the virus titer was determined by plaque assay.
  • MOCK - infected untreated cells 1 :1 - infected cells treated with the ECAS2 diluted 1 :1 , 100 mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2, 100 mI;
  • FIG. 3 Titer of the HSV-1 strain Kupka.
  • HSV-1 strain Kupka (MOI 0.01 ) was incubated with the test products for 2, 6, 8 or 12 h before the infection of Vero cells. The infected cells were collected at 24 hpi and the virus titer was determined by plaque assay. MOCK - cells infected with untreated virus; 1 : 1 - infected cells treated with the ECAS2 diluted 1 :1 , 100mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2, 100mI; ACV - infected cells treated with aciclovir, 100mM.
  • FIG. 4 Titer of the HSV-1 strain ANGpath.
  • ANGpath (MOI 0.01 ) was incubated with the test products for 2, 6, 8 or 12 h before the infection of Vero cells. The infected cells were collected at 24 hpi and the virus titer was determined by plaque assay. MOCK - cells infected with untreated virus; 1 :1 - infected cells treated with ECAS2 diluted 1 :1 , 100mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2, 100mI; ACV - infected cells treated with aciclovir, 100mM.
  • FIG. 5 Summary score of the ophthalmological evaluation of ECAS2 and Floxal ® treated rabbit eyes infected with Staphylococcus aureus. Rabbit eyes were treated within 6 days. 24, 48, 72, 96, 144 and 168 hpi the ophthalmological evaluation was performed. The main parameters of conjunctivitis were graded 1 , 2, 3 or 4 for each quadrant. The observations were summarized per group. The number of eyes per group n was 8.
  • Figure 6 Average score of the ophthalmological evaluation of ECAS2 and Floxal® treated rabbit eyes infected with Staphylococcus aureus. Rabbit eyes were treated for 6 days. 24, 48, 72, 96, 144 and 168 hpi the ophthalmological evaluation was performed. The main parameters of conjunctivitis were graded 1 , 2, 3 or 4 for each quadrant. The observations were expressed as average score per group. The number of eyes per group n was 8.
  • FIG. 7 Colony-forming units (CFUs) found in ECAS2 and Floxal ® treated rabbit eye conjunctivas infected with Staphylococcus aureus. Rabbit eyes were treated for 6 days. 24, 48, 72, 96, and 144 hpi the ophthalmological evaluation was performed. The observations were summarized per group. The number of eyes per group n was 8.
  • Pseudomonas aeruginosa Rabbit eyes were treated every hour from 6 to 19 h post infection. Following sacrifice of the rabbits, the number of viable Pseudomonas aeruginosa per 100 mg of cornea was quantified. The number of eyes per group n was 5. The present invention shall be further illustrated in more detail but not limited by the following examples.
  • Example 1 Preparation and characterization of electrochemically activated salt solutions
  • ECAS electrolysis reactors
  • Saturated sodium chloride solution stored in a tank was applied through a valve at a predetermined ratio to a flow of pure water for injection e.g. with a flow rate of 2.83 l/min and then pumped through the reactors.
  • the two activated solutions generated by the anode and the cathode were collected and mixed at a predetermined ratio to give pure ECAS.
  • borate and/or phosphate salts were added to the pure ECAS before dilution with water for injection.
  • Example 2 Stability of electrochemically activated salt solutions The stability of electrochemically activated salt solutions was evaluated by storing the obtained ECAS (see Table 1 ) in a closed, high-density polyethylene (HDPE) container at 20 °C.
  • ECAS electrochemically activated salt solutions
  • Table 2a Stability of ECAS 0, ECAS 1 and ECAS 2 over a period of 6 and 12 month
  • the Time Kill Antibacterial Test is an in-vitro test measuring the number of bacteria killed at different times after inoculation of ECAS in the bacterial suspension. The detailed results of this test on all ECAS samples at different storage times are reported in Table 2b, 2c, 2d
  • ECAS show good antibacterial activity.
  • the stability results show that ECAS 1 and ECAS 2, comprising salts of boric acid and salts of phosphoric acid, respectively, are more stable than ECAS 0 in terms of physicochemical parameters (Tab. 2a) and maintainance of antibacterial activity also after one year, as shown in detail in Tables 2c and 2d.
  • Example 3 In vitro antimicrobial activity of electrochemically activated salt solutions The in vitro antimicrobial activity of the ECAS 2 against bacteria, yeast and spores was tested. The tests were conducted in triplicate of each, a negative control (buffered sodium chloride-peptone solution), ECAS 2 and a reference product (Floxal ® , eyedrops, 0.3% ofloxacin, benzalkoniumchloride, water for injection), against 10 reference strains and 39 clinical isolates. Each microorganism sample was diluted to a starting concentration of at least 10 5 - 10 6 CFU/ml. Then, the negative control, the ECAS 2 and the reference product were inoculated with 0.1 ml each and each sample was mixed. At time intervals of 0, 15, and 30 min after inoculation, samples were taken and inactivated to determine the microbial survival.
  • the reduction in microorganism population was calculated by comparing the initial microbial concentration and the concentration at each incubation interval (both in CFU/mL). The results are shown in Table 3.
  • Streptococcus anginosus, Streptococcus pyogenes, Pseudomonas aeruginosa, E.coli, Enterobacter aerogenes, Candida albicans and Aspergillus brasiliensis were susceptible to ECAS 2.
  • the ECAS 2 showed high activity (inhibition of more than 50 %) at time 0 against 9/10 microorganisms. An inhibition of more than 90% was determined for 7 microorganisms.
  • Streptococcus anginosus, Streptococcus pyogenes, Pseudomonas aeruginosa, E.coli and Enterobacter aerogenes were susceptible to the reference product Floxal ® .
  • the reference product showed high activity (inhibition of more than 50 %) at time 0 against 5/10 microorganisms. An inhibition of more than 90% was determined for 3 microorganisms.
  • Candida albicans and Aspergillus brasiliensis remained viable (inhibition of less than 50%) during up to 30 min of incubation.
  • the 39 clinical isolates involved in the study were selected based on the incidence of the strains as collected from conjunctivitis in the medical microbiology laboratory within a one- month period. The most of them (34) were Staphylococcus aureus and MRSA, the rest, with lower incidence were E.coli (2), Pseudomonas aeruginosa (1 ), Acinetobacter pitii (1 ), and Serratia marcescenc (1 ). Staphylococcus aureus and MRSA
  • the ECAS 2 showed high activity (inhibition of more than 50 %) at time 0 against 30/34 of tested isolates. An inhibition of more than 90% was determined for 16/34 isolates of S. aureusMRSA.
  • the reference product showed high activity (inhibition of more than 50 %) at time 0 against 14/34 tested S. aureusMRSA isolates. An inhibition of more than 90% was determined for 1/34 isolates.
  • the reference product showed activity (inhibition of more than 90 %) against 32/34 tested isolates.
  • the ECAS 2 showed high activity (inhibition of more than 50 %) at time 0 against 2/2 of the tested E. coli isolates. An inhibition of more than 90% was determined for 2/2 isolates.
  • the ECAS 2 showed activity (inhibition of more than 99 %) against 2/2 tested E. coli strains at 15 minutes.
  • the reference product showed high activity (inhibition of more than 50 %) at time 0 against 2/2 of the tested E. coli isolates. An inhibition of more than 90% was determined for 0/2 isolates.
  • the reference product showed activity (inhibition of more than 90 %) against 2/2 tested isolates of E. coli at 15 minutes.
  • the ECAS 2 showed high activity of more than 90% for 1/1 isolate of Pseudomonas aeruginosa at 0 min.
  • the ECAS 2 showed activity (inhibition of more than 99 %) against 1/1 tested Pseudomonas aeruginosa strain.
  • the reference product showed high activity (inhibition of more than 50 %) against 1/1 and an inhibition of more than 90% against 0 isolates of Pseudomonas aeruginosa at time 0.
  • the reference product showed activity (inhibition of more than 90 %) against 1/1 tested isolates of Pseudomonas aeruginosa at 15 minutes.
  • the ECAS 2 showed high activity (inhibition of more than 50 %) at time 0 against 2/2 isolates of the listed Gram negative bacteria.
  • the ECAS 2 showed activity (inhibition of more than 99 %) against 2/2 isolates.
  • the reference product showed high activity (inhibition of more than 50 %) at time 0 against 2/2 of the listed Gram negative bacteria.
  • the reference product showed activity (inhibition of more than 90 %) against 1/2 tested isolates.
  • Vero cells were seeded in 24-well plates and treated with dilutions of the ECAS 2 Dil.1 :1 and Dil.1 :2, either:
  • the cells were infected with the HSV-1 strains Kupka and ANGpath at a multiplicity of infection (MOI) of 0.01.
  • the cells were collected 24 hours post infection (hpi) and the virus titer was determined by plaque assay. Briefly, the samples were serially diluted and plated onto one-day Vero cell-monolayers in 24- or 6-well tissue plates in duplicates. Afterwards, the cells were overlaid with 1% methylcellulose in normal growth media. 5 days post infection, the cells were fixed and stained with 2% crystal violet in 20% ethanol, and the individual plaques were counted to determine the virus titer in each sample. Samples without treatment (Mock, negative control) and samples treated with ACV (Acyclovir, 100 m ⁇ oI/I, reference control) were handled in the same manner. The test was performed in two independent experiments, where each of the samples was tested in parallel wells.
  • MOI multiplicity of infection
  • HSV-1 strains Kupka and ANGpath were incubated at a MOI of 0.01 with dilutions of the ECAS 2 either Dil.1 :1 or Dil.1 :2, in a final volume of 100 mI for either:
  • the ECAS 2 diluted 1 :2 did not inhibit virus replication to the extent observed at a dilution 1 : 1 . Nevertheless, when the cells were treated during the infection, a titer reduction by 3.26 Iog10 PFU/ml (p ⁇ 0.01 ) was detected compared to mock-treated infected cells.
  • Table 4 Reduction in viral titer of the HSV-1 strain Kupka according to test method A. MOCK - infected untreated cells; 1 :1 - infected cells treated with the ECAS2 diluted 1 :1 , 100 mI; 1 :2 - infected cells treated with the ECAS2 diluted 1 :2, 100 mI; ACV - infected cells treated with aciclovir, 100 mM;
  • the ECAS 2 diluted 1 :2 did not inhibit virus replication to the extent observed at a dilution of 1 : 1 . Nevertheless, when the cells were treated at 6 hpi, a reduction in titer by 2.24 Iog10 PFU/ml (p ⁇ 0.01 ) compared to mock-treated infected cells was detected.
  • a product is considered as mildly active against a virus in the case the virus titer is reduced at least by 1 Iog10 PFU/ml in comparison to the control.
  • a strong antiviral effect of the product is considered when the virus titer is reduced by at least 4 log 10 PFU/ml.
  • Our results indicate that treatment of cells with the ECAS 2 diluted 1 :1 during the infection or at early times post infection could reduce the viral titer at least by 4 Iog10 PFU/ml and this potential of the ECAS is not dependent on the HSV-1 strain.
  • the ECAS 2 according to the invention has the potential to reduce the viral titer, when cells are treated during the infection or at early times post infection.
  • Table 6 Reduction in viral titer of the HSV-1 strain Kupka according to test method B. MOCK - cells infected with untreated virus; 1 :1 - infected cells treated with ECAS2 diluted 1 :1 , 100 mI; 1 :2 - infected cells treated with ECAS2 diluted 1 :2, 100 mI; ACV - infected cells treated with aciclovir, 100 mM;
  • a total reduction in titer of the HSV-1 strain ANGpath was detected in infected cells treated with the ECAS 2 diluted 1 :1 for 2, 8 and 12 h.
  • the reduction in virus titer in infected cells treated with the ECAS 2 diluted 1 :2 at 6-12 h was even stronger in comparison to ACV treatment (Fig. 4).
  • Table 7 Reduction in viral titer of the HSV-1 strain ANGpath according to test method B. MOCK - cells infected with untreated virus; 1 :1 - infected cells treated with ECAS2 diluted 1 :1 , 100mI; 1 :2 - infected cells treated with ECAS2 diluted 1 :2, 100mI; ACV - infected cells treated with aciclovir, 100mM;
  • the ECAS 2 has the potential to reduce the viral titer, when cells are treated with the ECAS 2 during the infection or at early times post infection. Moreover, the ECAS 2 has the potential to reduce the viral titer, when virus is treated with the ECAS 2 for two hours and more before the infection.
  • Example 5 In vivo antimicrobial activity of electrochemically activated salt solutions
  • ECAS 2 The antimicrobial effect of ECAS 2 in vivo was examined in eye balls of young New Zealand albino female rabbits.
  • the conjunctiva of the rabbit right eye was injured under the condition of Isoflurane anesthesia.
  • Staphylococcus aureus DOC 845/1 for inoculation was prepared from an overnight suspension after centrifugation, washing in saline and appropriate dilution to a suspension of 10 6 CFU and was instilled (injection in a volume of 50 mI) to mimic a branch injury.
  • S. aureus was allowed to incubate for 48 hours.
  • Ophthalmological examinations were performed daily just before the first treatment, except for the fourth day of treatment.
  • the main parameter - conjunctival hyperaemia - was graded 1 , 2, 3 or 4 for each quadrant according to Draize eye test (Table 9) ( J. Draize et al., 1944 ). The scoring was performed by two persons; the left eye was used as a control.
  • Ophthalmological examination before the first treatment and at the final ophthalmological examination included also the cornea and the iris.
  • Table 9 Scale of weighted scores for grading the severity of conjunctiva lesions
  • Swabs were taken from the infected eye 48 hours after inoculation and every two days.
  • the swabs were transported in sterile transport media before dilution and cultured using spread plate method. Residual antimicrobial agent in the recovery agar could artificially depress the recovery of viable cells. For this reason, the residual antibacterial activity was inactivated by dilution as described below.
  • this rabbit had already a score of“0” when evaluated by the (168h).
  • the evaluation of the local finding was performed independently by a team of two veterinarians (24, 48, 72, 96, 144, 168 h) and complete evaluation by an ophthalmologist (192h). The discrepancy is probably the result of differences in the criteria set by these evaluators.
  • the ECAS2 group After four days of treatment the ECAS2 group showed effective clinical cure in 4/8 animals (score 0-1 ) whilst the Floxal ® treated group showed effective clinical cure in 6/8 animals. Eight days post infection (6 dosing days) complete clinical cure was observed in 6/8 animals of the ECAS 2 group whereas in the Floxal ® treated group absence of clinical slight symptoms of conjunctivitis was observed in 7/8 animals. The process of infection eradication was relatively fast not allowing to perform a comparison at more time points.
  • Table 12 Score for hyperemiae, chemosis and discharge score in the eradication phase of infection
  • the swabs were negative in 3/8 rabbits.
  • the focus lies on analyzing the activity of the ECAS 2 in comparison with that of Floxal ® by using rabbits with Staphylococcus aureus induced conjunctivitis.
  • the efficacy study was done in the right eye balls of young New Zealand albino female rabbits infected with log phase culture of the clinical isolate S. aureus DOC 845/1 .
  • the anti-conjunctivitis efficacy was evaluated by monitoring the symptoms and scoring of each group. At days 1 , 2, 3, 4, 6 and 7 ophthalmological evaluations were done, and the swabs tests for mean bacterial counts were taken every 2 nd day.
  • Pseudomonas aeruginosa is one of the most commonly isolated pathogens from contact lens-associated ulcerative incidents. Patients infected with P. aeruginosa develop severe ulcers and often require more extensive treatments than patients with infections caused by other pathogens. Corneal destruction during P. aeruginosa infection is rapid, and perforation and/or loss of vision is possible within 24 h.
  • the intrastromal injection of bacteria is not analogous, in terms of the route of inoculation, to the most common forms of human keratitis.
  • the invasion of tissue by bacteria from the corneal surface is the more natural means of initiating infection.
  • topical inoculations often fail to produce an infection or yield infections in an imprecise fashion (large variations in number of bacteria in the tissue) (O’Callaghan et al., 1999).
  • Intrastromal Pseudomonas aeruginosa was given to the right eye of 15 rabbits.
  • the treatment of Pseudomonas-infected corneas started 6 hours after infection based on clinical signs. Treatment products were administered every 60 min with 19 doses in total. The same treatment schedule was applied in group IV for evaluation of non-infected rabbits with the ECAS treatment.
  • Group I (infected without treatment - 1): treated with physiological saline
  • Group I infected with treatment - II: animals received treatments with the ECAS 2. 40 mI of ECAS 2 was sterilely instilled into the right conjunctival sac with a micropipette according to the schedule. The eye lids were gently closed for 10 - 15 seconds. The left eye served as the control.
  • Group III infected with treatment - III: animals received treatments with Floxal ® in a volume of 40 mI sterilely instilled into the right conjunctival sac with a micropipette according to the schedule. The eye lids were gently closed for 10 - 15 seconds. The left eye served as the control.
  • Group IV (not infected with treatment - IV): animals received treatments with 40 mI of ECAS 2 sterilely instilled into the right conjunctival sac with a micropipette according to the schedule. The eye lids were gently closed for 10 - 15 seconds. The left eye served as the control.
  • the corneas were aseptically removed, dissected, transferred to tubes, weighed and cut into multiple pieces.
  • the tissues were homogenized in an ice bath by a tissue homogenizer at 20 000 rpm twice for 30 sec in 0.5 mL of sterile phosphate-buffered saline and aliquots were serially diluted 10x in sterile buffered sodium chloride peptone solution.
  • the animals treated with the reference product were serially diluted in buffered sodium chloride peptone solution + 5% Tween + 0.3% Lecithin + 0.1 % Histidine for inactivation of residual reference product.
  • Samples from each dilution were plated in triplicate by pipetting 100 m ⁇ on Tryptone Soy agar (TSA) and Cetrimid agar and spreading, and incubated at 37 °C for 48 h. The viable CFUs were counted. The number of viable Pseudomonas aeruginosa was expressed per 100 mg of cornea (Table 14 and Figure 8).
  • the treatment of rabbit eyes infected with Pseudomonas aeruginosa from 6 to 19 h post infection with the ECAS 2 reduced the number of Pseudomonas aeruginosa organisms by approximately 1.6 log CFU/100 mg cornea compared to that of the untreated control group (from 4.4x10 6 to 1.1x10 5 CFU/100 mg cornea) (Fig. 8).
  • the % residual number of bacteria after treatment with ECAS2 was 2.6% of the control group.
  • Floxal ® reduced the number of bacteria from 4.4x10 6 to 30.6 CFU/100 mg of cornea, i.e. to a residual % number of bacteria equivalent to ⁇ 0.1 % relative to the saline control.
  • the present invention covers the following items:
  • Electrochemically activated salt solution comprising
  • a content of total chlorine of between 1 and 500 mg/I, preferably 100- 450 mg/I,
  • a content of chloride of between 2 and 8 g/l, preferably 3-7 g/l,
  • Electrochemically activated salt solution according to item 1 , which is stable over one year, preferably over two years, when stored in a closed, high-density polyethylene (HDPE) container at 20 °C.
  • ECAS Electrochemically activated salt solution
  • Electrochemically activated salt solution (ECAS) according to any of the
  • preceding items comprising at least one (salt of) boric acid, preferably in an amount of 0.01 to 1000 g/l, more preferably 0.1 -500 g/l.
  • Electrochemically activated salt solution (ECAS) according to any of the
  • Electrochemically activated salt solution (ECAS) according to any of the preceding items, wherein the total content of chlorite and chlorate ions is less than 10 mg/I.
  • Electrochemically activated salt solution (ECAS) according to any of the preceding items, wherein the total content of heavy metals and heavy metal ions is less than 10 pg/g, preferably less than 6 pg/g, and preferably the content of each individual heavy metal and heavy metal ion is preferably less than 0.5 pg/g.
  • Electrochemically activated salt solution (ECAS) according to any of the preceding items, further comprising at least one viscosity-increasing agent, such as a polymer.
  • Electrochemically activated salt solution (ECAS) according to item 8 wherein the polymer is selected from the group consisting of cellulose, cellulose derivatives, polysaccharides, such as glucosaminoglycans, polyvinyl alcohol, polyvinyl pyrrolidone, silica gel, and metasilicates of magnesium and/or aluminum.
  • Electrochemically activated salt solution (ECAS) according to any of the preceding items, which does not contain an additional therapeutically active agent, such as a drug.
  • Electrochemically activated salt solution (ECAS) according to any of the preceding items, which does not contain an additional preservative.
  • Pharmaceutical preparation comprising an electrochemically activated salt solution (ECAS) according to any of items 1 -1 1 . 13.
  • Pharmaceutical preparation according to item 12 further comprising at least one pharmaceutically acceptable excipient.
  • Electrochemically activated salt solution according to any of items 1 - 11 for use in treating infections, e.g. caused by bacteria, fungi and/or viruses.
  • Electrochemically activated salt solution for use according to item 14, wherein the bacteria and/or fungi are selected from the group consisting of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus,
  • Escherichia coli Staphylococcus epidermidis, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Enterobacter aerogenes, Streptococcus anginosus, Streptococcus pyogenes, Candida albicans, Aspergillus brasiliensis, Serratia marcescens and Acinetobacter pitii.
  • ECAS Electrochemically activated salt solution
  • Electrochemically activated salt solution for use according to item 14- 16 in treating eye infections.
  • Electrochemically activated salt solution for use according to any of items 14-17 in treating conjunctivitis, keratitis, blepharitis, and/or
  • Electrochemically activated salt solution for use according to any of items 14-18 in treating conjunctivitis, particularly bacterial conjunctivitis.
  • Electrochemically activated salt solution for use according to any of items 14-19, which is administered topically onto the eye, the lacrimal sac and/or the lid.
  • ECAS Electrochemically activated salt solution

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Inorganic Chemistry (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Electrochemistry (AREA)
  • Materials Engineering (AREA)
  • Metallurgy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une solution saline activée électrochimiquement (EGAS), sa production et son utilisation pour le traitement d'infections.
PCT/EP2019/068574 2018-07-12 2019-07-10 Solution saline activée électrochimiquement WO2020011870A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3104618A CA3104618A1 (fr) 2018-07-12 2019-07-10 Solution saline activee electrochimiquement
US17/259,458 US20210275579A1 (en) 2018-07-12 2019-07-10 Electrochemically activated salt solution
AU2019302997A AU2019302997B2 (en) 2018-07-12 2019-07-10 Electrochemically activated salt solution
KR1020217000792A KR20210031689A (ko) 2018-07-12 2019-07-10 전기화학적 활성화 염 용액
CN201980046368.2A CN112805064A (zh) 2018-07-12 2019-07-10 电化学活化的盐溶液
EP19740518.6A EP3820568A1 (fr) 2018-07-12 2019-07-10 Solution saline activée électrochimiquement
JP2021524110A JP2021531341A (ja) 2018-07-12 2019-07-10 電気化学的に活性化された塩溶液

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18183127.2 2018-07-12
EP18183127.2A EP3593862A1 (fr) 2018-07-12 2018-07-12 Solution saline activée électrochimiquement

Publications (1)

Publication Number Publication Date
WO2020011870A1 true WO2020011870A1 (fr) 2020-01-16

Family

ID=62948000

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/068574 WO2020011870A1 (fr) 2018-07-12 2019-07-10 Solution saline activée électrochimiquement

Country Status (8)

Country Link
US (1) US20210275579A1 (fr)
EP (2) EP3593862A1 (fr)
JP (1) JP2021531341A (fr)
KR (1) KR20210031689A (fr)
CN (1) CN112805064A (fr)
AU (1) AU2019302997B2 (fr)
CA (1) CA3104618A1 (fr)
WO (1) WO2020011870A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111904977A (zh) * 2020-08-18 2020-11-10 珠海市索利达医疗器械有限公司 一种用于皮肤及软组织抗感染治疗的组合物及其应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003050044A1 (fr) * 2001-12-10 2003-06-19 Radical Waters (Ip) (Pty) Limited Eau activee par un procede electrochimique pour le traitement des cystite
WO2004031077A2 (fr) 2002-10-03 2004-04-15 Sterilox Technologies International Limited Traitement electrochimique d'une solution saline aqueuse
US20040137078A1 (en) * 2000-01-12 2004-07-15 Ramin Najafi Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
WO2005065388A2 (fr) 2003-12-31 2005-07-21 Yodlee, Inc. Procede et appareil permettant de configurer et d'etablir une liaison de reseau a base de justificatifs d'identite surs entre un client et un service sur un reseau de transmission de donnees en paquets
WO2008089268A2 (fr) * 2007-01-16 2008-07-24 Puricore, Inc. Méthodes et compositions destinées au traitement de troubles associés à une infection et/ou à une inflammation
WO2009013019A2 (fr) 2007-07-26 2009-01-29 Azad Pharma Ag Préparations pharmaceutiques comprenant des solutions d'hypochlorite activées électrochimiquement
US20100330204A1 (en) 2009-06-17 2010-12-30 Apr Nanotechnologies S.A. Methods of Treating Outer Eye Disorders Using High Orp Acid Water and Compositions Thereof
EP2431056A1 (fr) * 2010-09-16 2012-03-21 Caliopa AG Composition pharmaceutique contenant une solution saline activée par électrochimie

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030185704A1 (en) * 2000-01-12 2003-10-02 Suzanne Bernard Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
CN101163491B (zh) * 2005-03-23 2017-04-19 奥古露丝创新科学公司 利用氧化还原电位水溶液治疗皮肤溃疡的方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040137078A1 (en) * 2000-01-12 2004-07-15 Ramin Najafi Physiologically balanced, ionized, acidic solution and methodology for use in wound healing
WO2003050044A1 (fr) * 2001-12-10 2003-06-19 Radical Waters (Ip) (Pty) Limited Eau activee par un procede electrochimique pour le traitement des cystite
WO2004031077A2 (fr) 2002-10-03 2004-04-15 Sterilox Technologies International Limited Traitement electrochimique d'une solution saline aqueuse
WO2005065388A2 (fr) 2003-12-31 2005-07-21 Yodlee, Inc. Procede et appareil permettant de configurer et d'etablir une liaison de reseau a base de justificatifs d'identite surs entre un client et un service sur un reseau de transmission de donnees en paquets
WO2008089268A2 (fr) * 2007-01-16 2008-07-24 Puricore, Inc. Méthodes et compositions destinées au traitement de troubles associés à une infection et/ou à une inflammation
WO2009013019A2 (fr) 2007-07-26 2009-01-29 Azad Pharma Ag Préparations pharmaceutiques comprenant des solutions d'hypochlorite activées électrochimiquement
US20100330204A1 (en) 2009-06-17 2010-12-30 Apr Nanotechnologies S.A. Methods of Treating Outer Eye Disorders Using High Orp Acid Water and Compositions Thereof
EP2431056A1 (fr) * 2010-09-16 2012-03-21 Caliopa AG Composition pharmaceutique contenant une solution saline activée par électrochimie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Clinical Ocular Pharmacology", 1 January 1989, BUTTERWORTH-HEINEMAN, REED PUBLISHING, Stoneham, MA, USA, article GERALD E LOWTHER: "Chapter 13 - Preparation used with contact lenses", pages: 338, XP055539528 *
EUROPEAN MEDICINES AGENCY ET AL: "Background review for the excipient boric acid", REVISION OF THE GUIDELINE ON 'EXCIPIENTS IN THE LABEL AND PACKAGE LEAFLET OF MEDICINAL PRODUCTS FOR HUMAN USE' (CPMP/463/00 REV. 1), 23 July 2015 (2015-07-23), pages 1 - 19, XP055538539, Retrieved from the Internet <URL:https://www.ema.europa.eu/documents/report/background-review-excipient-boric-acid-context-revision-guideline-excipients-label-package-leaflet_en.pdf> [retrieved on 20190107] *
R. M. S. THORN ET AL: "Electrochemically activated solutions: evidence for antimicrobial efficacy and applications in healthcare environments", EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES., vol. 31, no. 5, 2 August 2011 (2011-08-02), DE, pages 641 - 653, XP055537990, ISSN: 0934-9723, DOI: 10.1007/s10096-011-1369-9 *

Also Published As

Publication number Publication date
AU2019302997B2 (en) 2024-08-01
EP3820568A1 (fr) 2021-05-19
CA3104618A1 (fr) 2020-01-16
KR20210031689A (ko) 2021-03-22
AU2019302997A1 (en) 2021-02-18
JP2021531341A (ja) 2021-11-18
US20210275579A1 (en) 2021-09-09
EP3593862A1 (fr) 2020-01-15
CN112805064A (zh) 2021-05-14

Similar Documents

Publication Publication Date Title
US10668099B2 (en) Methods and compositions for treating conditions associated with infection and/or inflammation
US10632147B2 (en) Methods and compositions for treating inflammatory disorders
KR102224121B1 (ko) 포비돈-요오드를 포함하는 안과용 조성물
US20080287395A1 (en) Phospholipid Compositions for Contact Lens Care and Preservation of Pharmaceutical Compositions
EP3157507B1 (fr) Composition ophtalmique pour le traitement d&#39;une infection oculaire
US11738043B2 (en) Sodium chlorite compositions with enhanced antimicrobial efficacy and reduced toxicity
KR20190032629A (ko) 신규한 요오드포 조성물 및 사용 방법
US20070141091A1 (en) Biguanide ointment and method of treatment and prevention of infections
AU2019302997B2 (en) Electrochemically activated salt solution
US20180221407A1 (en) Ophthalmic compositions for therapeutic and prophylactic uses
KR20110104367A (ko) 무보존제 안과용 조성물
US20100204181A1 (en) N-halogenated amino acid formulations comprising phosphine or amine oxides
US10016375B2 (en) Materials and methods for controlling infections
CN107970211B (zh) 术前眼角膜冲洗液、制备方法及其应用
Olorode et al. Evaluation of Antimicrobial Effectiveness of Ophthalmic Drops Sold in Nigeria Pharmacy Stores and Market Places
JPWO2005072727A1 (ja) 点眼剤組成物
JPH04352728A (ja) 眼科用製剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19740518

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3104618

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021524110

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019302997

Country of ref document: AU

Date of ref document: 20190710

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019740518

Country of ref document: EP

Effective date: 20210212